Glaucoma is an ocular disorder associated with elevated ocular pressures which are too high for normal function and may result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by many ophthalmologists to represent the earliest phase of glaucoma.
Many of the drugs formerly used to treat glaucoma proved not entirely satisfactory. Indeed, few advances were made in the treatment of glaucoma since pilocarpine and physostigmine were introduced. A few .beta.-adrenergic blocking agents are effective in reducing intraocular pressure. While many of these agents are effective in reducing intraocular pressure, they also have other characteristics, e.g. local anesthetic activity, that are not acceptable for chronic ocular use because of the potential for corneal damage, directly as the result of the anesthesia, or indirectly by the presence of foreign particles that may go unnoticed in the anesthetized eye.
Timolol, a .beta.-adrenergic blocking agent, was found to reduce intraocular pressure and to be devoid of many unwanted side effects associated with pilocarpine and, in addition, to possess advantages over many other .beta.-adrenergic blocking agents, e.g. to be devoid of local anesthetic properties, to have a long duration of activity, and to display minimal tolerance.
However, known .beta.-adrenergic blocking agents have not been shown to demonstrate any meaningful oculoselectivity and, in spite of the low dose normally required for ocular administration, manifest their .beta.-blocking properties in extra ocular tissue, especially the pulmonary and cardiovascular systems to such an extent that they should not be administered to patients with pulmonary or cardiovascular ailments.
With this invention .beta.-adrenergic blocking properties have been discovered in a type of chemical structure not previously known to exhibit such properties and quite different from the traditional .beta.-blockers all or most of which have a 3-amino- 2-hydroxypropoxy or similar group.
The general type of chemical structure of the novel compounds of this invention is known.
Certain 6H-7,8-dihydrothiopyrano[3,2-d]-pyrimidines are disclosed in Belgian Patent No. 724745 as intermediates for the preparation of compounds with cardiovascular and coronary dilation activity, however, no suggestion is made of any .beta.-blocking activity for either the intermediates or the final products. Great Britain 2119368 discloses 6H-7,8-dihydrothiopyrano[3,2-d]pyrimidines with a very different substitution pattern on the nucleus when compared with the instant compounds. U.S. Pat. Nos. 3,318,883, 3,272,811, and 3,318,881 disclose dihydrothieno[3,2-d]pyrimidines.
Now, with the present invention there are provided compounds of similar structure with pronounced .beta.-blocking properties, some of which are oculoselective having little or no liability by way of local anesthesia or extra-ocular .beta.-blocking activity; pharmaceutical formulations of those compounds; methods of treating hypertension and elevated intraocular pressure with certain of these compounds; and processes for preparation of these compounds.
The principal difference between the claimed compounds and the compounds of the above references is that the claimed compounds have a hydrogen on the piperazine nitrogen and superior .beta.-blocking activity to the reference compounds which have a substituent such as alkyl, benzyl, cyclopropyl or the like on the piperazine nitrogen, as shown in the following table:
TABLE __________________________________________________________________________ Concentration (nM) To Block Binding of Ligand by 50% R.sup.1 R.sup.2 .beta..sub.1 .beta..sub.2 __________________________________________________________________________ ##STR2## CH.sub.3 H 680 314 C.sub.6 H.sub.5 H 290 73 CH.sub.2 C.sub.6 H.sub.5 H 479 242 ##STR3## H 590 73 CH.sub.3 CH.sub.2 C.sub.6 H.sub.5 0% @ 10,000 (1) 0% @ 10,000 (1) CH.sub.3 C.sub.2 H.sub.5 3% @ 10,000 (1) 27,000 CH.sub.3 ##STR4## 6% @ 10,000 (1) 8% @ 10,000 (1) C.sub.4 H.sub.9 -n CH.sub.3 4,300 4,800 C.sub.2 H.sub.4 OH CH.sub.3 7% @ 10,000 (1) 14% @ 10,000 (1) ##STR5## CH.sub.3 H 820 340 CH.sub.3 CH.sub.3 15% @ 10,000 (1) 24% @ 10,000 (1) ##STR6## C.sub.2 H.sub.5 H 300 140 C.sub.2 H.sub.5 CH.sub.3 2,403 1,042 __________________________________________________________________________ (1) % blocked at nM concentration shown; 50% blockade not achieved at reasonable concentrations.